Niemann-Pick Type C (NPC) disease is a genetic, neurodegenerative disorder which causes progressive deterioration of the nervous system.

It usually affects children by interfering with their ability to metabolize cholesterol. Adult onset may also occur. Large amounts of cholesterol accumulate within the liver, spleen, and brain. This metabolic disorder leads to a series of neurological problems that are ultimately fatal…until a treatment is found.

Learn more about the Niemann Pick Type C from the Parseghian family and other families on our YouTube page.

In 1997 medical researchers funded by the Parseghian Foundation identified the location of a gene called NPC1 that is abnormal in patients with Niemann-Pick Type C disease. The NPC1 gene is on chromosome 18 and is normally present in two copies in each cell of the body. However, alterations or mutations in this gene cause about 95 percent of cases of NPC disease.

In a second smaller group of patients with NPC, alternations in NPC1 do not cause the disease. Researchers suspect a second gene, called NPC2, may be responsible.

Niemann-Pick Type C disease is known as an autosomal recessive inherited condition. This means that each parent of an affected child has one functional NPC1 gene, plus one non-functional NPC1 (or more rarely, NPC2) gene. These parents are called carriers, or heterozygotes, and exhibit no signs or symptoms of the disease. Affected children inherit two non-functional NP-C genes from their parents.

In each pregnancy of a carrier couple, there is a one in four (25 percent) chance that they will both pass their non-functional NPC genes to a child who would then be affected. There is a one in two (50 percent) chance that only one of them would pass a non-functional gene. The child would then be a carrier like the parents. There is a 25 percent chance that both functional genes would be passed and the child would be neither a carrier nor affected with the disease.

NPC is a variable condition. This means that it can begin to affect individuals before birth or may not become evident until adulthood.

The classic form of the disease accounts for 50 to 60 percent of all cases. In this form, prenatal development and early childhood are usually normal, although jaundice may be present at or shortly after birth. Concern about behavioral problems may develop upon entry into school. The child will progressively develop loss of intellectual function, clumsiness, and difficulty with upward and downward eye movements.

In childhood, spleen or liver enlargement may be noted. Difficulties with speech (such as slurring), problems with swallowing, and in some cases, seizures may occur. Psychiatric disturbances may develop. Other symptoms may include sudden loss of muscle strength, which may vary from head nodding to complete collapse, abnormal posturing of the limbs, and lung complications.

Death from complications of the disease usually occurs in the teenage years or early adulthood. It is important to note that the early symptoms of NPC may vary significantly in childhood. Among the other symptoms children may experience are:

  • Liver failure without neurologic symptoms
  • Jaundice at birth
  • Early development of neurological problems
  • Low muscle tone
  • Delayed motor development beginning before age 2
  • Progressive liver failure starting in infancy
  • Early lung involvement without neurologic disease
  • Seizures

Late occurring cases typically have a less dramatic onset of symptoms. In these children and young adults, intellectual and psychiatric symptoms are the most significant.

Due to the wide variability of early symptoms of NPC, clinical diagnosis of the condition may be difficult. Physicians who suspect this diagnosis may proceed to specialized testing based on the presence of several symptoms.

Suspected patients usually have a small piece of skin removed (skin biopsy). The skin cells are grown in the laboratory and are tested for their ability to process cholesterol and for accumulation of cholesterol in certain locations in the cells. Results from both types of testing are needed to identify the classic and other forms of NPC and to eliminate other possible causes of the symptoms.

There are two labs in the United States that conduct diagnostic testing for Niemann-Pick Type C Disease:

  • Contact: John O’Brien, Mayo Clinic, Rochester, MN – Obrien.john@mayo.edu
  • Contact: David Wenger, Thomas Jefferson University – David.Wenger@jefferson.edu

With the identification of NPC1, it is now possible to identify changes in this gene. These changes, called mutations, affect how this gene works. In groups of NPC patients from Nova Scotia and Hispanics in southern Colorado and northern New Mexico, a common gene change has been identified. However, most patients with NP-C have unique mutations in the NPC1 gene. This makes it difficult to use DNA studies to make an initial diagnosis of the condition.

If laboratory testing reveals that the cholesterol processing and storage findings are consistent with NPC, it is possible to analyze the patient’s NPC1 gene for mutations through Mayo Clinic in Rochester, Minnesota. A blood or skin sample is obtained from the patient, and then the DNA, or genetic material, is collected from the cells in the sample. Laboratory studies of the DNA look for gene alterations that change the way the NPC protein functions. If changes or mutations are found, the information may be used to accurately determine whether other family members also have changes in their NPC genes. Sometimes it will not be possible to identify both genetic changes or mutations in the NPC1 gene pair in an affected individual.

Caution must be exercised when using DNA results from an affected family member for carrier testing in unaffected relatives. Because NPC is a variable disorder, unaffected younger siblings of the patient, or in some cases even unaffected older siblings, could have two copies of the genetic changes that cause the disease, but not yet have symptoms. Prior to testing, it is vital to discuss all of the implications of genetic testing for NPC with a medical geneticist or genetic counselor.

If an unaffected relative of an NPC patient, such as a sibling or cousin, were to be identified as a carrier, this would increase the risk for NPC in a future pregnancy for that person. It is somewhat possible to determine whether this individual’s partner is also a carrier to determine risk for the disease in a future pregnancy.

Contact Brittany Thomas at Mayo Clinic in Rochester, MN for more information on Niemann-Pick Type C DNA Analysis and Carrier Testing: thomas.brittany@mayo.edu

Treatment

While there not yet a specific treatment for NPC, supportive therapies are available. These include medications to control seizures, abnormal posturing of limbs and tremors. Physical, speech and occupational therapy are also used to help with daily functioning.

Identification of the NPC1 gene is helping researchers in the development of potential therapies. Already attempts have been made to correct the cell changes seen in NPC by using liver or bone marrow transplantation and by cholesterol-lowering medications. Thus far, these have had no effect on delaying the neurologic deterioration or progression of the disease.

Current Clinical Trials

Click here to access a great resource that compares the 3 current ongoing clinical trials. Below is a brief description of each trial:

Vtesse Clinical Trial with VTS-270

Vtesse is a rare disease company dedicated to developing drugs for the unmet medical needs of patients suffering from severe and life-threatening diseases. They are seeking regulatory approval for VTS-270, a well-characterized form of beta-cyclodextrin that has been evaluated in preclinical and clinical studies to treat patients with NPC disease. The company recently announced that it has raised a total of $42 million for Series A funding for the trials and is currently in the process of a Phase 2b/3 clinical trial being conducted in patients affected by NPC disease across the globe. Families interested in participating in the trial should contact a clinical trial site listed at thenpcstudy.com.

Additionally, a recent interview with Ben Machielse, CEO of Vtesse, that gives a great overview of the trials can be found at raredr.com/news/ceo-vtesse.

We thank Vtesse for their willingness to take this potential life-changing therapeutic through clinical trials and hope we can have it approved for children with NPC.

Vorinostat Clinical trial at the NIH

Researchers from Notre Dame and Cornell University have demonstrated the effectiveness of small molecule histone deacetylase inhibitors (HDACi) in correcting the NPC phenotype in human patient cells by increasing expression of the NPC1 protein.

The group is focusing on vorinostat, an FDA-approved anti-cancer treatment. The existing FDA approval of this drug has previously established its safety in humans and means that several expensive steps are not required. It is currently being tested for safety at the NIH.

Orphazyme

Orphazyme develops heat shock protein (HSP) based therapies for the treatment of degenerative diseases. Their lead program, OR-01, is an orally available small molecule inducer of the heat shock response. The molecule was well-tolerated in multiple clinical phase I studies and is now entering a phase II study in Niemann-Pick disease type C (NP-C).

Previous Clinical Trials

Zavesca

A drug trial has been concluded with Zavesca (OGT 918 or Miglustat) with NPC patients. This compound proved to be effective in NP-C mice in a research project funded by the Ara Parseghian Medical Research Foundation in slowing the progression of the disease. It has shown some positive benefits with some NPC children and adults.

The Phase 1-2 trial was conducted with NPC patients in the UK and the United States. There was an adult and a pediatric trial.

If you have questions about the trial, the results or about the drug Zavesca, please contact Dr. Marc Patterson at Mayo Clinic in Rochester, MN who was the trial coordinator: Patterson.marc@mayo.edu or Dr. J.E. Wraith in Manchester, UK.

Zavesca has not been FDA approved for NPC patients. It has however, been approved for use with another disease. Consequently, Zavesca is being taken by a number of NPC patients off label, depending of whether or not their insurance companies will cover the cost as it is very expensive.

Important Information for Patients taking Zavesca

Miglustat animal toxicology data:

Long term (two year) animal toxicity studies of miglustat have recently been reported. Mice given oral miglustat at doses of 210 (16 times the human dose), 420 and 840/500 mg/kg/day developed diarrhea, abdominal swelling and rectal prolapse. Microscopic examination of the large intestine showed inflammatory lesions. At the highest doses (840/500 mg/kg/day – 65/38 times the human dose) there was an increased number of tumors in the large intestine. Rats given the same doses of miglustat for two years did not develop such changes.

Male rats given miglustat in doses of 30, 60 and 180 mg/kg/day had an increased incidence of benign Leydig cell (testicular) tumors. These rats normally have a much higher incidence of Leydig cell tumors than humans. There was no increase in tumors in other organs.

We understand that many families will be concerned by these reports, and wish to place these in perspective:

  • No cases of bowel or testicular tumors have been reported in humans taking miglustat (which has now been available in clinical trial and practice for many years)
  • The doses of drug used in these animal studies are many times higher than those taken by humans.
  • The toxic effects reported may be species specific, and not necessarily relevant to humans.
  • Similar findings are not uncommon in toxicology studies.
  • We suggest that careful monitoring of gastrointestinal side effects such as is already performed, with further investigation for individuals who have persistent symptoms despite change in diet, dosage reduction or use of loperamide, is appropriate for individuals taking miglustat. You should speak to your physician directly to discuss any concerns that have not been addressed by this message.

Sincerely,

Marc C. Patterson, MD, FRACP
Pediatric Neurology
Mayo Clinic
Rochester, Minnesota, USA

Dr. J.E. Wraith (Consultant Paediatrician)
Willink Biochemical Genetics Unit
Royal Manchester Children’s Hospital
Hospital Road, Manchester M27 4HA
United Kingdom